Carboxy isatin hydrazones and their esters as Shp2 inhibitors

Abstract

Protein tyrosine phosphatase (PTP) Shp2 is a non-receptor PTP that involved in cell signaling and regulation of cell proliferation, differentiation, and migration. Shp2 mediates activation of kinases that are involved in the pathogenesis of human carcinoma. A high throughput screen identified compounds that inhibit the PTP Shp2. Several compounds were identified that selectively inhibit Shp2 over Shp1 with low to sub-micromolar activity. Also disclosed are methods of inhibiting a protein tyrosine phosphatase in a cell and treating cancer through selective inhibition of Shp2.

What is claimed is: 
     
       1. A compound having a formula (IV); 
       
         
           
           
               
               
           
         
         wherein R 1  is F; and 
         wherein R 2  is selected from the group consisting of COOCH 3 , CO 2 H, salts thereof, and CO 2   − .N + H 2 (CH 3 )(CH 2 CHOH) 4 CH 2 OH). 
       
     
     
       2. A method of treating a neoproliferative disease in an animal comprising the step of administering to a patient in need thereof an effective amount of a compound having the formula (V): 
       
         
           
           
               
               
           
         
         wherein R 1  is F; and 
         wherein R 2  is selected from the group consisting of COOCH 3 , CO 2 H, salts thereof, and CO 2   − .N + H 2 (CH 3 )(CH 2 CHOH) 4 CH 2 OH); 
         wherein the neoproliferative disease is leukemia, glioblastoma, prostate cancer, lung cancer, gastric cancer, colorectal cancer, neuroblastoma, melanoma, or breast cancer. 
       
     
     
       3. The method of  claim 2 , further comprising administering a therapeutically effective amount of IFN-γ sequentially or in combination with the compound having the formula (V). 
     
     
       4. The method of  claim 3 , wherein the IFN is administered at 100 U/ml and the compound having the formula (V) is administered at between 6.25 μM and 12.5 μM. 
     
     
       5. The method of  claim 2 , wherein the leukemia is juvenile myelomonocytic leukemia, B-cell precursor acute lymphoblastic leukemia, chronic myelogenous leukemia, or acute myelogenous leukemia.